Cultures of skin fibroblasts from normal individuals, individuals with genetic disorders predisposing to a high risk of cancer, cancer patients, as well as cells transformed in culture, are utilized in evaluating the relationship between radiation-induced chromosomal DNA damage, deficient DNA repair, cancer susceptibility and malignant neoplastic transformation. An increased incidence of chromatid damage after x-irradiation during G2 phase of the cell cycle is associated with both a predisposition to cancer and malignant transformation and may provide the basis for a test for cancer susceptibility. A genetic basis for this radiosensitivity is suggested from studies with somatic cell hybrids between normal and malignant cells. The chromosomal radiosensitivity appears to result from deficient DNA repair during G2-prophase. Another aspect of this project is to develop a reproducible transformation system with human epidermal keratinocytes as an in vitro model for following the progression of biologic and biochemical changes leading to neoplastic transformation. An associated problem is to identify and quantify cytomorphic changes diagnostic of neoplastic transformation and determine their functional basis.